Transcranial direct current stimulation (tDCS) is a technique used to modify cognition by modulating underlying cortical excitability via weak electric current applied through the scalp. Although many studies have reported positive effects with tDCS, a number of recent studies highlight that tDCS effects can be small and difficult to reproduce. This is especially the case when attempting to modulate performance using single applications of tDCS in healthy participants. Possible reasons may be that optimal stimulation parameters have yet to be identified, and that individual variation in cortical activity and/or level of ability confound outcomes. To address these points, we carried out a series of experiments in which we attempted to modulate performance in fluency and working memory probe tasks using stimulation parameters which have been associated with positive outcomes: we targeted the left inferior frontal gyrus (LIFG) and compared performance when applying a 1.5 mA anodal current for 25 min and with sham stimulation. There is evidence that LIFG plays a role in these tasks and previous studies have found positive effects of stimulation. We also compared our experimental group (N = 19–20) with a control group receiving no stimulation (n = 24). More importantly, we also considered effects on subgroups subdivided according to memory span as well as to more direct measures of executive function abilities and motivational levels. We found no systematic effect of stimulation. Our findings are in line with a growing body of evidence that tDCS produces unreliable effects. We acknowledge that our findings speak to the conditions we investigated, and that alternative protocols (e.g., multiple sessions, clinical samples, and different stimulation polarities) may be more effective. We encourage further research to explore optimal conditions for tDCS efficacy, given the potential benefits that this technique poses for understanding and enhancing cognition.

Introduction

Transcranial direct current stimulation (or tDCS) is a non-invasive form of brain stimulation which is used to modulate cognitive performance by applying a weak electric current via electrodes placed on the scalp. Early studies measuring effects of tDCS on motor cortical excitability suggested that the applied current can cause directional changes in the resting membrane potentials underneath the electrodes—with predominant depolarization under the anode (known as anodal tDCS) vs. hyperpolarization under the cathode (cathodal tDCS; de Berker et al., 2013). It is widely assumed that effects on cortical excitability map on to cognitive effects, with anodal vs. cathodal tDCS improving vs. worsening the cognitive function of targeted brains regions. However, though widely assumed, this might not necessarily be the case. Current flows between the electrodes with complex effects that are poorly understood. Moreover, an important confounding factor modulating the impact of tDCS may be individual variation in cortical activity and/or level of ability (for reviews, see Miniussi et al., 2013; Horvath et al., 2015; Li et al., 2015; Westwood and Romani, 2017; Westwood et al., 2017). These are widely cited as explanations for a number of recent reports of negative, inconsistent, and/or small effects linked to single applications of tDCS especially in healthy participants (see Horvath et al., 2015; Mancuso et al., 2016; Westwood et al., 2017). Our study will contribute to clarify the scope of tDCS effects by considering tasks that tax executive selection abilities, mediated by the frontal lobes, and where positive, but inconsistent, effects have been reported before. We will consider effects on the whole participant group, but crucially also on subgroups subdivided according to (a) general performance and control abilities; (b) working memory span; and (c) motivation levels to see whether these variables affect tDCS outcomes.[…]

Some scientists are enthusiastic about the technology and say it has substantially fewer side effects than psychotropic medications. Numerous studies suggest it may improve our ability to learn pretty much anything, and there does seem to be evidence that a mild shock to the brain can help treat several psychiatric disorders.

Clinical trials are currently testing tDCS to treat a long list of disorders, including depression, pain, insomnia, Parkinson’s disease, schizophrenia, and addiction. A community of biohackers and self-experimenters has arisen in garages and online forums to build their own devices, or you can order a kit and test the technology on yourself.

But other researchers are more skeptical, doubting whether tDCS is as safe and effective as its champions claim. Despite promising lab results, none of the medical benefits have been verified by the FDA, and recent studies have called into question the technology’s ability to affect brain activity at all. Critics express concern about small study sizes and placebo effects, as well as the potential for side effects such as skin burns.

Jason Forte, a cognitive neuroscientist at the University of Melbourne, says he is particularly concerned about the potential dangers of using tDCS in the home. “There is risk of skin damage at the site of the electrode if the device is not used correctly. Poorly designed devices used in the wrong way could compromise heart function, although this has not been reported.”

Within the walls of academia, this debate is normal. A new drug or device arises every decade or so, exciting researchers and capturing the imagination of the public. Before it is released, scientists conduct hundreds of studies to figure out if the technique is safe, how best to administer it, and what it might be most useful for.

However, because of its relative safety and ease to build, tDCS has bypassed much of the usual review process and jumped from the lab to the living room. Private start-ups, such as The Brain Stimulator, TransCranial Technologies, and Halo Neuroscience, now sell DIY tDCS devices to curious self-experimenters and desperate patients. This shift has alarmed some researchers and regulatory experts, while others say they see no harm in sharing the technology.

How Brain Stimulation Works

With tDCS, the brain is zapped using a simple, consistent electrical current—typically 1 to 2 milliamps—for 20 to 30 minutes a day. The stimulation feels like a tingling or mild stinging at the site of the electrode. Neurons communicate through electrical and chemical signals. Scientists think the small amount of current neurons receive from tDCS makes them more likely to fire an electrical pulse, which results in a neurotransmitter being released into the brain.

tDCS is just one of several types of mild electrical brain stimulation. Other options include transcranial alternating current stimulation (tACS) and cranial electrotherapy stimulation (CES). In tACS, the keyword is “alternating.” In contrast to tDCS, the current in tACS constantly changes, oscillating between positive and negative. Scientists think that tACS works not by changing individual neurons, but by shifting the electrical frequency of the whole brain, which can optimize it for different states, like sleep or attention.

The current is also pulsed in a related technology, CES. Fisher Wallace, a company that sells CES devices, claims that the technology can increase neurochemical levels in the brain, including serotonin, but there is little evidence this is true. Of the three, it is the only device that is FDA-approved to treat depression, anxiety, and insomnia. But it was on the market before the FDA required proof of efficacy for class III medical devices, so it has not faced the same scrutiny that such devices face today.

tDCS has garnered more attention from researchers than the other types of brain stimulation, including ongoing clinical trials, and consequently more self-experimenters trying to mimic them.

Devices’ Claims Haven’t Been Thoroughly Tested

Michael Oxley was inspired to create his first brain stimulator device after reading aNew Scientist article on tDCS in 2012. A mechanical engineer, he hoped that mildly shocking his brain would increase his energy levels and improve his concentration. Five years later, Oxley has sold tens of thousands of tDCS headsets through his company, foc.us, which claim to “enhance alertness, boost focus and increase capacity to learn” and even “help you run further and faster.”

However, Oxley admits foc.us’s devices have not undergone any formal outside testing or clinical trials, and instead base their statements on self-experimentation and the wider scientific literature.

These statements about cognitive and physical performance are allowed by the FDA because they do not make any medical assertions. But Anna Wexler, a biomedical ethicist at the University of Pennsylvania, says they can be regulated by the Federal Trade Commission.

“[The FTC has] taken action against a number of companies making cognitive enhancement claims, both in the supplement world but also in the brain training world, so they’ve shown a willingness to kind of get involved,” she says. “They have not taken any action against a tCDS company, but in practice, in principle they could.”

Oxley emphasized he does not advertise their product to treat any psychiatric conditions, not just for fear of FDA retaliation, but because he feels it would be irresponsible. However, in reviews for foc.us’s devices, several customers report using the product to treat their depression. Wexler’s research supports this; in an upcoming study, she reveals that a third of home users administer the technology to self-medicate for conditions like depression.

The Potential Benefits of tDCS

Marom Bikson, a professor of biomedical engineering at The City College of New York, says that on its own, tDCS doesn’t do very much. Its real value comes when it is combined with learning. He recommends using the technology before or during learning a new activity, like playing the piano.

Neurons that fire together, wire together. By increasing the likelihood that a neuron will fire, tDCS helps the brain to forge new connections while it learns, a process called plasticity. This ability to impact learning is why tDCS is marketed as having such a broad range of potential uses.

“When you apply direct current stimulation, you can change ongoing plasticity. Not generate plasticity, but change plasticity that’s already ongoing,” says Bikson. “The direct current stimulation can boost that plasticity, so basically making the learning more effective.”

Bikson says with this type of functional targeting, it doesn’t really matter where the sponges and electrodes are placed, because only the neurons undergoing plasticity will be affected by tDCS.

In contrast, for conditions like anxiety and depression, researchers aim to increase activity in a specific area of the brain, the dorsolateral prefrontal cortex, that is underactive in people with depression. Stimulating this area with daily tDCS brings the neurons’ activity back up to a normal level, which is thought to help boost people’s mood.

A large-scale trial published earlier this year showed that tDCS performed better than placebo in treating depression. These results imply that tDCS really can improve depression symptoms, but the study also showed it is not as effective as traditional medications like SSRIs.

What Could Go Wrong

Areas just a few millimeters apart can have very different functions. With tDCS, the sponges that go on the scalp span several centimeters, so it’s difficult to ensure you’re stimulating the right area. Some researchers have expressed concerns about off-target effects of tDCS, particularly when treating psychiatric disorders, which requires activation of a particular region. The brain is like real estate: it’s all about location, location, location. Off-target effects are especially a concern for DIY brain stimulators who may not have a background in neuroanatomy.

“You’re affecting large swaths of neurons that then have downstream effects in their relationship with other neuronal populations and networks, so where you place the electrodes is really critical,” says Tracy Vannorsdall, a neuropsychologist at Johns Hopkins University School of Medicine. “We know that very small changes in the electrode montage—where we’re placing them on the brain—can have significant different effects in terms of cognitive outcomes.”

Studies have shown that increasing function in one area of the brain can actually impair performance in a different area. Less dramatic but perhaps more pressing are reports of home users experiencing burns or skin damage at the site of the electrodes.

Another concern is that the technique may not do anything at all. Many studiesreport no effect either behaviorally or in terms of brain activity using tDCS. In perhaps the most unique test of the technology, scientists demonstrated that only 10 percent of the electrical current penetrated the skull of a cadaver to reach its brain. These findings suggest tDCS has far less of an impact on the brain than researchers originally hoped, and possibly not enough to make any meaningful difference in neurons’ behavior.

So, Should You Do It?

Interested in trying it yourself? Instead of putting down a couple hundred dollars for your own device, neuropsychologist Vannorsdall recommends joining one of the 700 tDCS clinical trials listed on clinicaltrials.gov, which recruit both patients and healthy people. “I think right now that it’s just too early for people to be experimenting on themselves,” she says.

But Bikson, the biomedical engineer, says self-experimentation may not be such a bad thing. Five years ago, his “knee-jerk reaction [as] the researcher in the academic ivory tower [was] this is my toy, don’t touch it.” But now his stance has softened. “I’m really really hesitant to tell someone who is really suffering or whose loved one is suffering to do or not do something,” he says. “I’m not going to endorse it, but I’m not going to condemn them. Obviously, many of us in the clinical and basic research communities believe these technologies can be effective.”[…]

Abstract

Background

Recovery of voluntary movement is a main rehabilitation goal. Efforts to identify effective upper limb (UL) interventions after stroke have been unsatisfactory. This study includes personalized impairment-based UL reaching training in virtual reality (VR) combined with non-invasive brain stimulation to enhance motor learning. The approach is guided by limiting reaching training to the angular zone in which active control is preserved (“active control zone”) after identification of a “spasticity zone”. Anodal transcranial direct current stimulation (a-tDCS) is used to facilitate activation of the affected hemisphere and enhance inter-hemispheric balance. The purpose of the study is to investigate the effectiveness of personalized reaching training, with and without a-tDCS, to increase the range of active elbow control and improve UL function.

Methods

This single-blind randomized controlled trial will take place at four academic rehabilitation centers in Canada, India and Israel. The intervention involves 10 days of personalized VR reaching training with both groups receiving the same intensity of treatment. Participants with sub-acute stroke aged 25 to 80 years with elbow spasticity will be randomized to one of three groups: personalized training (reaching within individually determined active control zones) with a-tDCS (group 1) or sham-tDCS (group 2), or non-personalized training (reaching regardless of active control zones) with a-tDCS (group 3). A baseline assessment will be performed at randomization and two follow-up assessments will occur at the end of the intervention and at 1 month post intervention. Main outcomes are elbow-flexor spatial threshold and ratio of spasticity zone to full elbow-extension range. Secondary outcomes include the Modified Ashworth Scale, Fugl-Meyer Assessment, Streamlined Wolf Motor Function Test and UL kinematics during a standardized reach-to-grasp task.

Discussion

This study will provide evidence on the effectiveness of personalized treatment on spasticity and UL motor ability and feasibility of using low-cost interventions in low-to-middle-income countries.

Background

Stroke is a leading cause of long-term disability. Up to 85% of patients with sub-acute stroke present chronic upper limb (UL) sensorimotor deficits [1]. While post-stroke UL recovery has been a major focus of attention, efforts to identify effective rehabilitation interventions have been unsatisfactory. This study focuses on the delivery of personalized impairment-based UL training combined with low-cost state-of-the-art technology (non-invasive brain stimulation and commercially available virtual reality, VR) to enhance motor learning, which is becoming more readily available worldwide.

A major impairment following stroke is spasticity, leading to difficulty in daily activities and reduced quality of life [2]. Studies have identified that spasticity relates to disordered motor control due to deficits in the ability of the central nervous system to regulate motoneuronal thresholds through segmental and descending systems [3, 4]. In the healthy nervous system, the motoneuronal threshold is expressed as the “spatial threshold” (ST) or the specific muscle length/joint angle at which the stretch reflex and other proprioceptive reflexes begin to act [5, 6, 7]. The range of ST regulation in the intact system is defined by the task-specific ability to activate muscles anywhere within the biomechanical joint range of motion (ROM). However, to relax the muscle completely, ST has to be shifted outside of the biomechanical range [8].

After stroke, the ability to regulate STs is impaired [3] such that the upper angular limit of ST regulation occurs within the biomechanical range of the joint resulting in spasticity (spasticity zone). Thus, resistance to stretch of the relaxed muscle has a spatial aspect in that it occurs within the defined spasticity zone. In other joint ranges, spasticity is not present and normal reciprocal muscle activation can occur (active control zone; [4] Fig. 1). This theory-based intervention investigates whether recovery of voluntary movement is linked to recovery of ST control.

Fig. 1Spatial thresholds (STs) in healthy and stroke participants. a The tonic stretch reflex threshold (TSRT) can be regulated throughout a range (filled bar) that exceeds the biomechanical range of the joint (open bar). Relaxation and active force can be produced at any angle within the biomechanical range. b The intersection of the diagonal line with the zero-velocity line defines the TSRT. In healthy subjects, TSRT lies outside of the biomechanical range of the joint (arrow) during the relaxed state. c In patients with stroke, TSRT may lie within the biomechanical range in the relaxed state, defining the joint angle at which spasticity begins to appear (spasticity zone). In the other joint ranges, spasticity is not present (active zone)

We also consider that inter-hemispheric balance is disrupted after stroke, interfering with recovery. UL motor function depends on the modulation of inter-hemispheric inhibition between cortical areas via transcallosal projections [9, 10] and descending projections to fingers, hand and arm [11]. Unilateral hemispheric damage reduces activity in the affected hemisphere while activity in the unaffected hemisphere increases [12], becoming more dominant. UL recovery may relate to rebalancing of inter-hemispheric inhibition [13] using, for example, anodal transcranial direct current stimulation (a-tDCS) over the affected hemisphere [14, 15]. a-tDCS is considered a safe technique with transient adverse effects, such as slight scalp itching or tingling and/or mild headaches, that are not expected to impede the patient’s ability to participate in the training protocol [16].

The underlying idea of this proposal is that recovery of voluntary movement is tightly linked to the recovery of threshold control. We propose an intervention that combines current knowledge about motor learning and disorders in ST control. The intervention involves personalized UL reach training designed according to the spatial structure of motor deficits of an individual, with excitatory a-tDCS over the sensorimotor areas of the affected hemisphere. […]

Abstract

Transcranial electrical brain stimulation using weak direct current (tDCS) or alternating current (tACS) is being increasingly used in clinical and experimental settings to improve cognitive and motor functions in healthy subjects as well as neurological patients. This review focuses on the therapeutic value of transcranial direct current stimulation for neurorehabilitation and provides an overview of studies addressing motor and non-motor symptoms after stroke, disorders of attention and consciousness as well as Parkinson’s disease.

Background

The past 10 years have seen an increased clinical and experimental focus on noninvasive electrical brain stimulation as an innovative therapeutic approach to support neurorehabilitation. This entails the application of either transcranial direct current stimulation (tDCS), or less commonly, transcranial alternating current stimulation (tACS). Typically, up to 0.8 A/m² is used for up to 40 min per single stimulation session [1]. The electrical current partially penetrates the underlying structures and affects nerve cells, glia and vessels in the stimulated brain area [1] [2]. Early animal experiments during the 1960s and 1970s on the effects of weak DC stimulation demonstrated an excitement-induced change of neurons lasting several hours after the end of the stimulation [3] [4]. Therapeutic studies of the 1970s, at that time mainly concerning the treatment of depression, did not yield any success, which in retrospect could be attributed to the stimulation parameters used. In 2 000 key experiments by Nitsche and Paulus on polarity-related excitability changes in the human motor system after transcranial application of tDCS led to a renewed interest in the approach [5]. The authors documented increased cortical excitability measured by the amplitude of motor-evoked potentials in healthy volunteers after anodal stimulation above the motor cortex lasting at least 9 min [6]. Reversing the direction of stimulation (cathodal tDCS) resulted in a decrease in motor-evoked potential. In addition to the concept of pure excitability modulation, a large number of studies demonstrate modulation of neuroplasticity by tDCS in various ways, including basic scientific and mechanistic findings regarding improvement of synaptic transmission strength [7] [8] [9], long-term influence on learning processes and behavior [10] [11], as well as a therapeutic approach to improve function in neurological and psychiatric disorders associated with altered or disturbed neuroplasticity (overview in [12]). In particular, simultaneous application of tDCS together with different learning paradigms, such as motor or cognitive training, appears to produce favorable effects in healthy subjects and in various patient groups [11] [13].

The following review presents the effects of tDCS on the improvement in the function of some neurological disease patterns which are regularly the focus of neurorehabilitative treatment. This especially includes stroke. In addition, we shall refer to a current database of clinical studies containing a comprehensive list of scientific and clinical studies of tDCS in the treatment of neurological and psychiatric disorders [14].

Post-stroke Motor Impairment

Stroke is one of the primary causes worldwide of permanent limitations of motor function and speech. Despite intensive rehabilitation efforts, approx. 50% of stroke patients remain limited in their motor and speech capabilities [15] [16] [17]. Current understanding of the mechanisms of tDCS is largely based on data documented for the human motor system. The reasons for this include the presence of direct and easily objectifiable measurement criteria (for example, motor-evoked potential, fine motor function), as well as anatomical accessibility of brain motor regions for non-invasive stimulation. Therefore, it is not surprising that the clinical syndrome of stroke with the frequent symptom of hemiparesis as a “lesion model of the pyramidal tract” received significant scientific interest with respect to researching the effects of tDCS, as evidenced by the numerous scientific publications since 2005 ([Fig. 1]). In contrast to earlier largely mechanistic studies, in the past 5 years there has been a trend toward studies addressing clinically-oriented therapeutic issues. […]

Fig. 2 Illustration of the 3 typical brain stimulation montages exemplified by tDCS above the motor cortex. In example a, the anode (red) is placed above the ipsilesional motor cortex, and the cathode (blue) is located on the contralateral forehead. Example b shows the cathode placed above the motor cortex of the non-lesioned hemisphere, and the anode is placed on the contralateral forehead. Example c illustrates bihemispheric montage, with the anode located above the ipsilesional motor cortex, and the cathode placed above the motor cortex of the non-lesioned hemisphere. The white arrow shows the intracerebral current flow. The goal of these 3 arrangements is to modulate the interaction between both motor cortices by changing the activity of one or both hemispheres c.

Abstract

Crossover designs are used by a high proportion of studies investigating the effects of transcranial direct current stimulation (tDCS) on motor learning. These designs necessitate attention to aspects of data collection and analysis to take account of design-related confounds including order, carryover, and period effects. In this systematic review, we appraised the method sections of crossover-designed tDCS studies of motor learning and discussed the strategies adopted to address these factors. A systematic search of 10 databases was performed and 19 research papers, including 21 experimental studies, were identified. Potential risks of bias were addressed in all of the studies, however, not in a rigorous and structured manner. In the data collection phase, unclear methods of randomization, various lengths of washout period, and inconsistency in the counteracting period effect can be observed. In the analytical procedures, the stratification by sequence group was often ignored, and data were treated as if it belongs to a simple repeated-measures design. An inappropriate use of crossover design can seriously affect the findings and therefore the conclusions drawn from tDCS studies on motor learning. The results indicate a pressing need for the development of detailed guidelines for this type of studies to benefit from the advantages of a crossover design.

In a recent clinical trial we demonstrated the analgesic effects of anodal transcranial direct current stimulation (tDCS) in patients with spinal cord injury (SCI); however, the positive impact of tDCS on pain was not paralleled by an improvement in quality of life or other related clinical scales. Here we discuss the reasons of such negative results and present hypotheses that could explain why tDCS had no impact on patients’ quality of life, while their average level of pain decreased. We will also discuss how these negativefindings can help to design future clinical trial using tDCS to treat individuals with chronic pain.

tDCS is an alternative but relevant therapeutic option to manage pain and stimulate motor recovery in patients with SCI. This non-invasive neuromodulation technique has been shown to significantly and sustainably reduce pain if applied repeatedly in various pain syndromes (Fregni et al., 2006a,b; Valle et al., 2009; Sakrajai et al., 2014; Castillo-Saavedra et al., 2016). In our previous study we assessed the effects of motor (M1) anodal tDCS on pain relief, as well as satisfaction with life as measured by the Satisfaction with Life Scale (SWLS) (Diener et al., 1985; Dijkers, 1999), quality of life through mental state (Kroenke et al., 2001) with the Patient Health Questionnaire (PHQ-9), and symptoms of depression with the Beck Depression Inventory. The study comprised two phases; the first one consisted of five tDCS sessions with behavioral assessments completed at baseline, at the end of the five stimulation sessions, at 1-week and 3-month follow-up. The second phase started after the end of the 3-month follow-up period of the Phase I. During this second phase, patients who agreed to continue received 10 sessions of tDCS (applied once daily for 2 weeks) in order to evaluate the effects of adding a second phase of treatment. Assessments were performed after 5 and 10 stimulation sessions and at 2, 4, and 8-week follow-up. While pain was found to be reduced in the active treatment group, and this effect was maintained up to 4 weeks after the last tDCS session, quality of life and mood remained unchanged throughout the entire duration of the protocol for both active and sham groups.

Several hypotheses could explain why anodal M1 tDCS had no influence on mood or satisfaction with life: (1) M1 may not be an appropriate target to modulate mood or satisfaction with life; (2) the primary outcome was pain and therefore this study was not designed to specifically detect change in such scales; (3) the SWLS and PHQ-9 may not be accurate or sensitive enough to detect changes due to tDCS treatment.

Based on the current tDCS literature and the present understanding of pain sensitization mechanisms, the sensorimotor cortex is the most relevant area to target when aiming at treating pain (Castillo Saavedra et al., 2014). By stimulating this specific brain region, anodal tDCS can reduce or reverse the detrimental reorganization of the neural pain network occurring as a consequence of chronic pain mechanisms (Seifert and Maihöfner, 2009; Henderson et al., 2011; Gustin et al., 2012). Several studies have shown that M1 stimulation, using either tDCS or other non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS), leads to local and distant neural effects that result in pain reduction (Lefaucheur, 2016). For instance, stimulating M1 may counteract the lack of inhibition from M1, that could also be associated with pain reduction (Botelho et al., 2016; Caumo et al., 2016). In addition, neuroimaging studies have demonstrated that tDCS could also induce changes in thalamic, insula and cingulate activity (Yoon et al., 2014; Simis et al., 2015), known to be related to pain processing (Treede et al., 1999). Regarding quality of life and life satisfaction, significant improvements have been observed when tDCS was applied over the dorsolateral prefrontal cortex (DLPFC), rather than M1 stimulation, in various conditions (Fregni et al., 2006b; Mori et al., 2011; Viana et al., 2014; Liu et al., 2016). Indeed, the prefrontal region has been shown to be a better modulator for mood, and quality of life (Schaffer et al., 1983; Drevets, 1998). The region of interest, and subsequently the network to target, is one of the most important parameters when designing a clinical trial, based on the symptoms or behaviors to improve. In this context it is essential to evaluate the brain behavior relationship with the appropriate tools when designing a clinical trial. This can be seen as a decisional pyramid between: symptom(s)—network to target—behavioral correlates. In this context it is critical to have a clear a priori hypothesis and to select the appropriate clinical scale(s) accordingly. A recent framework developed by researchers from National Institute of Mental Health (NIMH), called the research domain criteria (RDoC) is useful for such analysis.

Sankarasubramanian et al. (2017) assessed the effects of anodal tDCS applied on two distinct sites on functional connectivity. They found site-specific effects of M1 tDCS vs. tDCS applied over the DLPFC on functional connectivity between the thalamus and the cortex. Both M1 and DLPFC tDCS increased functional connectivity between the ventroposterolateral nucleus of the thalamus and the sensorimotor cortices; however, the connectivity was greater with M1 tDCS. On the other hand, both M1 and DLPFC tDCS increased functional connectivity between the medial dorsal nucleus of the thalamus and the motor cortex, but only DLPFC tDCS modulated functional connectivity between this nucleus and affective cortices (Sankarasubramanian et al., 2017); highlighting the network-specific effect of site-specific tDCS. From a clinical perspective, similar observations have been made. Roizenblatt et al. (2007) compared the effects of anodal tDCS applied over the left DLPFC with M1 tDCS on pain level and sleep in patients with fibromyalgia (Roizenblatt et al., 2007). M1 stimulation was the only condition associated with reduced pain, and it improved sleep quality as well. On the other hand, DLPFC tDCS did not modulate pain level and it worsened sleep efficiency, stressing the site-specificity of tDCS clinical effects. In addition Boggio et al. (2008) showed that in healthy subjects only M1 stimulation leads to a change of somatosensory perception (Boggio et al., 2008). Indeed, it appears than stimulating M1 mainly influences lateral thalamic projections that process sensory-discriminative information and are paralleled with significant clinical improvement (Antal et al., 2010; Mori et al., 2010), while the stimulation of other sensorimotor structures, such as the somatosensory cortex or the premotor, and supplementary motor areas, have failed to induce similar analgesic effects (Koyama et al., 1993; Hirayama et al., 2006).

Recently, the authors of a randomized controlled trial, notably arguing that they had performed the first and only sufficiently powered trial testing the analgesic effects of tDCS in participants with SCI, concluded that anodal M1 tDCS was ineffective to alleviate or reduce pain in this specific condition when applied for 5 days (Luedtke et al., 2015). In this trial, they compared a group of patients receiving active tDCS for 5 days followed by cognitive training for 4 weeks, to a group of patients who received sham tDCS for 5 days followed by the same cognitive training for 4 weeks. However, such results need to be assessed with caution given that the main area of stimulation (i.e., M1) and the behavioral training that was performed following tDCS (i.e., cognitive behavioral therapy) targeted two different networks. The authors found a significant decrease in pain scores in both groups (sham and active M1 tDCS) after cognitive behavioral therapy, but there were no differences between active and sham tDCS. This result is not surprising since the cognitive behavioral therapy activates mainly prefrontal neural circuits, while M1 tDCS stimulates the sensori-motor network. In this case, an important concept needs to be considered when designing a protocol; it is not only the anatomical region of stimulation that needs to be determined but the anatomical region plus the cortical engagement. For instance, if M1 is targeted with tDCS but a behavioral stimulation activates prefrontal circuits, it is expected that M1 tDCS would have minor, or no effects at all, on enhancing the effects of behavioral stimulation since they target two different circuits. It is suggested that combined therapies should target the same circuit to be additive. Indeed, tDCS could prime the brain targeted circuit before a therapy as it has been shown with combined tDCS and robotic upper limb therapy in cerebral palsy (Friel et al., 2017).

As noted above, it is essential to understand the mechanisms and networks involved in a specific pathology in order to appropriately treat it. It is now well-acknowledged that tDCS modulates not only the area stimulated but also the entire neural network. For instance, by means of neuroimaging studies (fMRI and Positron Emission Tomography—PET-scan), anodal M1 tDCS has been shown to activate ipsilateral motor areas (e.g., primary, supplementary, or premotor cortices) as well as contralateral or long-distance areas (e.g., frontal cortex, somatosensory regions, posterior parietal cortex) and subcortical areas (anterior cingulate cortex) in healthy controls (Lang et al., 2005; Kwon et al., 2008; Kim et al., 2012). These areas are altered in chronic pain syndromes (Baliki et al., 2011). Yoon et al. (2014) used PET-scan to assess brain metabolism after M1 tDCS in participants with chronic pain. They reported that tDCS induces increased metabolism in the medulla and decreased metabolism in the left DLPFC (Yoon et al., 2014). These various neuroimaging studies demonstrate the effect of M1 tDCS on cortical and sub-cortical pain-related network activity. New multichannel-tDCS devices may be even more effective given that they could target and stimulate different areas involved in the same neural network. Preliminary mechanistic studies have shown the superiority of such approaches as compared to conventional dual tDCS (Fischer et al., 2017). Indeed, it has been demonstrated that, as compared to conventional M1 tDCS montage, a single session of novel eight-electrode montage targeting M1 and its associated network induced more than twice as much increase in M1 excitability, measured by resting state fMRI (Fischer et al., 2017). This result shows the possible superiority of such novel network-based multi-channel tDCS approaches; however, behavioral effects still need to be demonstrated.[…]

tDCS act directly—with focused precision—on the areas of the brain that govern the physical and mental functions in need of rehabilitation. Through the use of these devices we’re able to greatly enhance the efficacy of rehabilitation itself.

Abstract

Objectives

To evaluate effects of somatosensory stimulation in the form of repetitive peripheral nerve sensory stimulation (RPSS) in combination with transcranial direct current stimulation (tDCS), tDCS alone, RPSS alone, or sham RPSS + tDCS as add-on interventions to training of wrist extension with functional electrical stimulation (FES), in chronic stroke patients with moderate to severe upper limb impairments in a crossover design. We hypothesized that the combination of RPSS and tDCS would enhance the effects of FES on active range of movement (ROM) of the paretic wrist to a greater extent than RPSS alone, tDCS alone or sham RPSS + tDCS.

Materials and Methods

The primary outcome was the active ROM of extension of the paretic wrist. Secondary outcomes were ROM of wrist flexion, grasp, and pinch strength of the paretic and nonparetic upper limbs, and ROM of wrist extension of the nonparetic wrist. Outcomes were blindly evaluated before and after each intervention. Analysis of variance with repeated measures with factors “session” and “time” was performed.

Results

After screening 2499 subjects, 22 were included. Data from 20 subjects were analyzed. There were significant effects of “time” for grasp force of the paretic limb and for ROM of wrist extension of the nonparetic limb, but no effects of “session” or interaction “session x time.” There were no significant effects of “session,” “time,” or interaction “session x time” regarding other outcomes.

Conclusions

Single sessions of PSS + tDCS, tDCS alone, or RPSS alone did not improve training effects in chronic stroke patients with moderate to severe impairment.